Proteome Heterogeneity in Colorectal Cancer
Lay Cheng Lim* and Yang Mooi Lim
Tumor heterogeneity is an important feature of colorectal cancer (CRC)
manifested by dynamic changes in gene expression, protein expression, and
availability of diﬀerent tumor subtypes. Recent publications in the past 10
years have revealed proteome heterogeneity between diﬀerent colorectal
tumors and within the same tumor site. This paper reviews recent research
works on the proteome heterogeneity in CRC, which includes the
heterogeneity within a single tumor (intratumor heterogeneity), between
diﬀerent anatomical sites at the same organ, and between primary and
metastatic sites (intertumor heterogeneity). The potential use of proteome
heterogeneity in precision medicine and its implications in biomarker
discovery and therapeutic outcomes will be discussed. Identiﬁcation of the
unique proteome landscape between and within individual tumors is
imperative for understanding cancer biology and the management of CRC
It is well-accepted that tumor heterogeneity is the main factor that
contributes to the development of precision medicine in colo-
rectal cancer (CRC).
Tumor heterogeneity in CRC refers to
heterogeneity within a single tumor (intratumor heterogeneity),
between diﬀerent anatomical sites at the same organ, and be-
tween primary and metastatic sites (intertumor heterogeneity)
These tumor heterogeneities underlie the diﬀerent
phenotypic behaviors in CRC.
CRC tumor heterogeneity has been reported at the genetic
and protein levels.
Numerous researches based on genomic
and transcriptomic proﬁles have been done to reveal the exten-
sive intertumor heterogeneity in CRC.
To resolve tumor het-
erogeneity for the advancement of precision diagnosis, progno-
sis, and treatment response, two independent research groups
have proposed four transcriptional consensus molecular sub-
types (CMSs) and ﬁve tumor archetypes.
The CMSs were
associated with distinctive histopathological features, which in-
clude the CMS1 (microsatellite instability-immune inﬁltration,
14%) frequently found in right-sided tumors, CMS2 (canonical,
37%) that is mainly found in left-sided tumors, CMS3 (metabolic,
13%), and CMS4 (mesenchymal, 23%).
The tumor archetypes
were identiﬁed based on the analysis of the epithelial cell and
Centre for Cancer Research
Faculty of Medicine and Health Sciences
University of Tunku Abdul Rahman
stroma-derived transcripts mixture, de-
noted as SSC, dARE (depleted in AU-
rich elements), CIN, goblet, and stroma,
which showed distinct gene expression
pattern, signaling pathways, and involve-
ment of diﬀerent cell components.
Subtyping of CRC into homogeneous
tumor archetypes allows the identiﬁ-
cation of archetype-speciﬁc prognostic
biomarker panels that can improve pre-
diction of prognosis in CRC.
covery of multiple pathways involvement
in CRC tumorigenesis in diﬀerent tumor
subtypes mandates a “multi-molecular”
perspective for developing therapies to
Multi-region sequencing of biopsies
from the primary tumors and liver metas-
tases showed 30–40% of identiﬁed so-
matic mutations failed to be detected in
every sequenced region.
Recent ﬁndings reported genomic pro-
ﬁling of 349 individual glands obtained from 15 colorectal tumors
showed uniformly high intratumor heterogeneity (ITH) and sub-
clone mixing in distant regions.
The results have shown the
ITH in CRC originated from a primordial tumor where the clonal
and subclonal alterations occurred in the early stage of tumor
growth and have expanded to the distant area.
discovery of genetic heterogeneity from the previous studies,
biomarkers derived from the genomics research cannot fully ex-
plain the prognostic diﬀerences among CRC patients due to the
epigenetic eﬀects, alternative splicing, and posttranscriptional
modiﬁcation processes occurred in CRC.
Guinney and col-
leagues demonstrated that no single genomic aberration and sig-
nal transduction cascade is limited to a CRC subtype.
highlights the poor genotype–phenotype correlations in CRC
where tumors harboring commonly assumed driver events in
CRC still vary markedly in their biological functions.
gene expression-based subtypes are only partially recapitulated
at the protein level. In addition, the poor correlation between the
mRNA transcript and protein abundance in CRC reinforced the
importance of proteomic analysis in CRC.
Proteins are the ulti-
mate products and functional vectors of genes that contribute di-
rectly to the cellular phenotype. Hence, research on proteomics
could provide more explanations on the mechanism about the
progression and prognosis of CRC that may not be revealed by
the genomics studies.
The proteome heterogeneity in CRC is still poorly understood.
Understanding and knowledge of the proteome heterogeneity are
very important, as it will aid in developing proteogenomics to in-
crease the knowledge of the complex biological system during
the initiation and progression of CRC. This could help to improve
biomarker discovery and therapeutic outcomes. Recently, the ﬁrst
Proteomics 2018, 1700169
2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1700169 (1 of 9)